Yersinia pestis is the causative agent of pneumonic plague. Development of a vaccine that protects against inhalation infection and ensuing pneumonic plague is of the utmost importance. Prior vaccination strategies, focusing on the development of a protective humoral response, have generated effective protection against the bubonic form of infection, however these strategies have provided incomplete protection against pneumonic infection. Recent investigations have revealed that F1-V protein subunit vaccination affords protection early during the course of a pneumonic infection in non-human primates, however late breakthrough of organism is found even in the presence of high Yersinia-specific antibody titers. We hypothesize that a vaccine that generates cell mediated immunity, particularly type 1 cytokine-producing (TH1) V protein-specific CD4+ T cells, in addition to stimulating humoral immunity, will protect against a pneumonic infection with Y. pestis. Aim 1 will generate class II MHC multimers for tracking V specific CD4+ T cells. It will also optimize vaccination regimens for production of memory V specific CD4+ T cells and determine if they are protective against lethal aerosol challenge. Aim 2 studies the protective immune response produced by a live, attenuated vaccine strain that is known to generate protection against pneumonic plague.